Abstract 4120: Adherent-to suspension transition by hematopoietic factors in metastatic dissemination of circulating tumor cells

Abstract

Abstract Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during the metastatic cascade remains elusive. We discovered a biological phenomenon referred to as Adherent-to-Suspension Transition (AST) that reprograms adherent cells into suspension cells via aberrant induction of hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. During dissemination, tumor microenvironment triggers epigenetic alteration of AST factors in the invasive front of solid tumors to evoke spontaneous cell-matrix dissociation, acquire anoikis resistance, and bypass immune surveillance of CTCs, however, in the absence of lineage differentiation and EMT. Using mouse models and de novo metastatic patient specimens, we uncovered how Adherent-Suspension Plasticity (ASP) dictates anchorage plasticity during the dissemination and colonization process within the metastatic cascade. Finally, we demonstrate therapeutic strategies that target AST factors to specifically abrogate CTC formation and suppress distant metastases. Together, these findings underscore an important early mechanism of how cancer cells spread and highlight novel targets for the development of anti-metastatic therapy. Furthermore, AST opens unexplored scenarios how reprogramming anchorage dependency orchestrates physiological events such as development, organ morphogenesis and immune cell activation. Citation Format: Hyun Woo Park. Adherent-to suspension transition by hematopoietic factors in metastatic dissemination of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4120.